XENICAL is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. XENICAL is also indicated to reduce the risk for weight regain after prior weight loss. XENICAL is indicated for obese patients with an initial body mass index (BMI) ≥30 kg/m ² or ≥27 kg/m ² in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia).

Table 1 illustrates body mass index (BMI) according to a variety of weights and heights. The BMI is calculated by dividing weight in kilograms by height in meters squared. For example, a person who weighs 180 lbs and is 5 ^' 5 ^" would have a BMI of 30.

Table 1 Body Mass Index (BMI), kg/m ²Conversion Factors: Weight in lbs ÷ 2.2 = weight in kilograms (kg) Height in inches × 0.0254 = height in meters (m) 1 foot = 12 inches

• XENICAL is a reversible inhibitor of gastrointestinal lipases indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. ( 1)
• XENICAL is also indicated to reduce the risk for weight regain after prior weight loss. ( 1)

Table 1

• One 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal). ( 2)
• Advise patients to take a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. ( 2)
• Distribute the daily intake of fat, carbohydrate, and protein over three main meals. ( 2)
• Advise patients to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition. ( 2)
• Take the vitamin supplement at least 2 hours before or after the administration of XENICAL, such as at bedtime. ( 2)
• For patients receiving both XENICAL and cyclosporine therapy, administer cyclosporine 3 hours after XENICAL. ( 2)
• For patients receiving both XENICAL and levothyroxine therapy, administer levothyroxine and XENICAL at least 4 hours apart. ( 2)

The recommended dose of XENICAL is one 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal).

The patient should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. The daily intake of fat, carbohydrate, and protein should be distributed over three main meals. If a meal is occasionally missed or contains no fat, the dose of XENICAL can be omitted.

Because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition [see Warnings and Precautions (5.1)] . The vitamin supplement should be taken at least 2 hours before or after the administration of XENICAL, such as at bedtime.

For patients receiving both XENICAL and cyclosporine therapy, administer cyclosporine 3 hours after XENICAL.

For patients receiving both XENICAL and levothyroxine therapy, administer levothyroxine and XENICAL at least 4 hours apart. Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function.

Doses above 120 mg three times a day have not been shown to provide additional benefit.

Based on fecal fat measurements, the effect of XENICAL is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48 to 72 hours.

XENICAL is contraindicated in:

• Pregnancy [see Use in Specific Populations (8.1)]
• Patients with chronic malabsorption syndrome
• Patients with cholestasis
• Patients with known hypersensitivity to XENICAL or to any component of this product

• Pregnancy ( 4, 8.1)
• Chronic malabsorption syndrome ( 4)
• Cholestasis ( 4)
• Known hypersensitivity to XENICAL or to any component of this product ( 4)

• XENICAL has drug interactions and can decrease vitamin absorption. ( 5.1, 7)
• Take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition. ( 5.1)
• Rare cases of severe liver injury with hepatocellular necrosis or acute hepatic failure have been reported. ( 5.2)
• Patients may develop oxalate nephrolithiasis and oxalate nephropathy following treatment with XENICAL. Monitor renal function in patients at risk for renal insufficiency. Discontinue XENICAL if oxalate nephropathy develops. ( 5.3)
• Substantial weight loss can increase the risk of cholelithiasis. ( 5.4)
• Exclude organic causes of obesity (eg, hypothyroidism) before prescribing XENICAL. ( 5.5)
• Gastrointestinal events may increase when XENICAL is taken with a diet high in fat (>30% total daily calories from fat). ( 5.5)

XENICAL may interact with concomitant drugs including cyclosporine, levothyroxine, warfarin, amiodarone, antiepileptic drugs, and antiretroviral drugs [see Drug Interactions (7)].

Data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Therefore, XENICAL and cyclosporine should not be simultaneously coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 3 hours before or after XENICAL in patients taking both drugs. In addition, in those patients whose cyclosporine levels are being measured, more frequent monitoring should be considered.

Patients should be strongly encouraged to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate nutrition because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene [see Dosage and Administration (2), and Adverse Reactions (6.1)] . In addition, the levels of vitamin D and beta-carotene may be low in obese patients compared with non-obese subjects. The supplement should be taken once a day at least 2 hours before or after the administration of XENICAL, such as at bedtime.

Weight-loss may affect glycemic control in patients with diabetes mellitus. A reduction in dose of oral hypoglycemic medication (e.g., sulfonylureas) or insulin may be required in some patients [see Clinical Studies (14)] .

There have been rare postmarketing reports of severe liver injury with hepatocellular necrosis or acute hepatic failure in patients treated with XENICAL, with some of these cases resulting in liver transplant or death. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jaundice, dark urine, light-colored stools, or right upper quadrant pain) while taking XENICAL. When these symptoms occur, XENICAL and other suspect medications should be discontinued immediately and liver function tests and ALT and AST levels obtained.

Some patients may develop increased levels of urinary oxalate following treatment with XENICAL. Cases of oxalate nephrolithiasis and oxalate nephropathy with renal failure have been reported. Monitor renal function when prescribing XENICAL to patients at increased risk for oxalate nephropathy, including patients with renal impairment and in those with a history of hyperoxaluria or calcium oxalate nephrolithiasis. Discontinue XENICAL in patients who develop oxalate nephropathy.

Substantial weight loss can increase the risk of cholelithiasis. In a clinical trial of XENICAL for the prevention of type 2 diabetes, the rates of cholelithiasis as an adverse event were 2.9% (47/1649) for patients randomized to XENICAL and 1.8% (30/1655) for patients randomized to placebo.

Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing XENICAL.

Patients should be advised to adhere to dietary guidelines [see Dosage and Administration (2)] . Gastrointestinal events [see Adverse Reactions (6.1)] may increase when XENICAL is taken with a diet high in fat (>30% total daily calories from fat). The daily intake of fat should be distributed over three main meals. If XENICAL is taken with any one meal very high in fat, the possibility of gastrointestinal effects increases.

Most common treatment emergent adverse reactions (≥5% and at least twice that of placebo) include oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation and fecal incontinence. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact the Safety Call Center at 1-888-236-5445 or FDA at 1‑800‑FDA‑1088 (1-800-332-1088) or www.fda.gov/medwatch.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in patients.

Commonly Observed (based on first year and second year data)

Gastrointestinal (GI) symptoms were the most commonly observed treatment-emergent adverse events associated with the use of XENICAL in the seven double-blind, placebo-controlled clinical trials and are primarily a manifestation of the mechanism of action. (Commonly observed is defined as an incidence of ≥5% and an incidence in the XENICAL 120 mg group that is at least twice that of placebo.)

Table 2 Commonly Observed Adverse Events

Adverse Event	Year 1		Year 2
	XENICAL Treatment designates XENICAL three times a day plus diet or placebo plus diet % Patients (N=1913)	Placebo % Patients (N=1466)	XENICAL % Patients (N=613)	Placebo % Patients (N=524)
Oily Spotting Oily discharge may be clear or have a coloration such as orange or brown.	26.6	1.3	4.4	0.2
Flatus with Discharge	23.9	1.4	2.1	0.2
Fecal Urgency	22.1	6.7	2.8	1.7
Fatty/Oily Stool	20.0	2.9	5.5	0.6
Oily Evacuation	11.9	0.8	2.3	0.2
Increased Defecation	10.8	4.1	2.6	0.8
Fecal Incontinence	7.7	0.9	1.8	0.2

In general, the first occurrence of these events was within 3 months of starting therapy. Overall, approximately 50% of all episodes of GI adverse events associated with XENICAL treatment lasted for less than 1 week, and a majority lasted for no more than 4 weeks. However, GI adverse events may occur in some individuals over a period of 6 months or longer.

Discontinuation of Treatment

In controlled clinical trials, 8.8% of patients treated with XENICAL discontinued treatment due to adverse events, compared with 5.0% of placebo-treated patients. For XENICAL, the most common adverse events resulting in discontinuation of treatment were gastrointestinal.

Other Adverse Clinical Events

The following table lists other treatment-emergent adverse events from seven multicenter, double-blind, placebo-controlled clinical trials that occurred at a frequency of ≥2% among patients treated with XENICAL 120 mg three times a day and with an incidence that was greater than placebo during year 1 and year 2, regardless of relationship to study medication.

Table 3 Other Treatment-Emergent Adverse Events From Seven Placebo-Controlled Clinical Trials

Body System/Adverse Event	Year 1		Year 2
	XENICAL Treatment designates XENICAL 120 mg three times a day plus diet or placebo plus diet % Patients (N=1913)	Placebo % Patients (N=1466)	XENICAL % Patients (N=613)	Placebo % Patients (N=524)
– None reported at a frequency ≥2% and greater than placebo
Gastrointestinal System
Abdominal Pain/Discomfort	25.5	21.4	–	–
Nausea	8.1	7.3	3.6	2.7
Infectious Diarrhea	5.3	4.4	–	–
Rectal Pain/Discomfort	5.2	4.0	3.3	1.9
Tooth Disorder	4.3	3.1	2.9	2.3
Gingival Disorder	4.1	2.9	2.0	1.5
Vomiting	3.8	3.5	–	–
Respiratory System
Influenza	39.7	36.2	–	–
Upper Respiratory Infection	38.1	32.8	26.1	25.8
Lower Respiratory Infection	7.8	6.6	–	–
Ear, Nose & Throat Symptoms	2.0	1.6	–	–
Musculoskeletal System
Back Pain	13.9	12.1	–	–
Pain Lower Extremities	–	–	10.8	10.3
Arthritis	5.4	4.8	–	–
Myalgia	4.2	3.3	–	–
Joint Disorder	2.3	2.2	–	–
Tendonitis	–	–	2.0	1.9
Central Nervous System
Headache	30.6	27.6	–	–
Dizziness	5.2	5.0	–	–
Body as a Whole
Fatigue	7.2	6.4	3.1	1.7
Sleep Disorder	3.9	3.3	–	–
Skin & Appendages
Rash	4.3	4.0	–	–
Dry Skin	2.1	1.4	–	–
Reproductive, Female
Menstrual Irregularity	9.8	7.5	–	–
Vaginitis	3.8	3.6	2.6	1.9
Urinary System
Urinary Tract Infection	7.5	7.3	5.9	4.8
Psychiatric Disorder
Psychiatric Anxiety	4.7	2.9	2.8	2.1
Depression	–	–	3.4	2.5
Hearing & Vestibular Disorders
Otitis	4.3	3.4	2.9	2.5
Cardiovascular Disorders
Pedal Edema	–	–	2.8	1.9

Table 4 illustrates the percentage of adult patients on XENICAL and placebo who developed a low vitamin level on two or more consecutive visits during 1 and 2 years of therapy in studies in which patients were not previously receiving vitamin supplementation.

Table 4 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Nonsupplemented Adult Patients With Normal Baseline Values - First and Second Year)

	Placebo Treatment designates placebo plus diet or XENICAL plus diet	XENICAL
Vitamin A	1.0%	2.2%
Vitamin D	6.6%	12.0%
Vitamin E	1.0%	5.8%
Beta-carotene	1.7%	6.1%

Table 5 illustrates the percentage of adolescent patients on XENICAL and placebo who developed a low vitamin level on two or more consecutive visits during the 1-year study.

Table 5 Incidence of Low Vitamin Values on Two or More Consecutive Visits (Pediatric Patients With Normal Baseline Values All patients were treated with vitamin supplementation throughout the course of the study)

	Placebo Treatment designates placebo plus diet or XENICAL plus diet	XENICAL
Vitamin A	0.0%	0.0%
Vitamin D	0.7%	1.4%
Vitamin E	0.0%	0.0%
Beta-carotene	0.8%	1.5%

In the 4-year XENDOS study, the general pattern of adverse events was similar to that reported for the 1- and 2-year studies with the total incidence of gastrointestinal-related adverse events occurring in year 1 decreasing each year over the 4-year period.

In clinical trials in obese diabetic patients, hypoglycemia and abdominal distension were also observed.

Pediatric Patients

In clinical trials with XENICAL in adolescent patients ages 12 to 16 years, the profile of adverse reactions was generally similar to that observed in adults.

The following adverse reactions have been identified during postapproval use of XENICAL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to XENICAL exposure.

• Rare cases of increase in transaminases and in alkaline phosphatase and hepatitis that may be serious have been reported. There have been reports of hepatic failure observed with the use of XENICAL in postmarketing surveillance, with some of these cases resulting in liver transplant or death [see Warnings and Precautions (5.2)] .
• Rare cases of hypersensitivity have been reported with the use of XENICAL. Signs and symptoms have included pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis. Very rare cases of bullous eruption have been reported.
• Rare cases of leukocytoclastic vasculitis have been reported. Clinical signs include palpable purpura, maculopapular lesions, or bullous eruption.
• Acute oxalate nephropathy after treatment with XENICAL has been reported in patients with or at risk for renal disease [see Warnings and Precautions (5.3)] .
• Pancreatitis has been reported with the use of XENICAL in postmarketing surveillance. No causal relationship or physiopathological mechanism between pancreatitis and obesity therapy has been definitively established.
• Lower gastrointestinal bleeding has been reported in patients treated with XENICAL. Most reports are nonserious; severe or persistent cases should be investigated further.